ABSTRACT Despite improvements in care for individuals with traumatic brain injury (TBI), clinicians have no neuroprotective treatment options for TBI. Moreover, investigators have limited ability a priori to predict mortality after TBI. Estradiol (E2) and progesterone (PRO) are well known for their neuroprotective qualities when studied in pre-clinical TBI models. However, our independent clinical data suggest relative increases in endogenous sex hormones occur after TBI that are derived from extra-gonadal sources and are the result of amplified aromatization pathways. These pathways use TNF? to produce E2 and are linked with mortality and poor outcome. The literature indicates that E2 accumulation may reflect a complex systemic response to injury that is initiated by the sympathetic nervous system (SNS) and perpetuated by SNS-induced inflammation, leading to amplified E2 production that is associated with systemic compromise, non-neurological organ dysfunction (NNOD) and increased mortality and poor outcome risk. Our body of work shows E2 and its extra- gonadal genomic transcription factor TNF? are important mortality predictors post-TBI and are associated with systemic complications that contribute to poor outcome. The dichotomy between animal studies and phase III randomized clinical trials (RCTs) for PRO specifically illustrate important questions requiring further study to reconcile if/how PRO might be a viable neuroprotective treatment option for subpopulations with TBI and to understand if/how E2 & TNF? levels can predict heterogeneity of treatment effects (HTE) with PRO therapy. Our central hypothesis is that serum E2 & TNF-?, reflect the systemic response to TBI, are novel indicators of baseline risk for mortality/poor outcome, and are sensitive indicators of variable PRO effects. E2 & TNF? may be effective in characterizing those with very high/low risk (regardless of treatment) as well as those who might benefit or be harmed by PRO. Using data and samples from the ProTECT III study and the BioProTECT trial, we have a unique opportunity to delineate biological heterogeneity and other contributors to the null findings treatment result. These cohorts provide a rigorously developed clinical research platform from which to test the hypothesis that systemic E2, & TNF-?, reflect the systemic response to TBI and can serve as an indicator of HTE to PRO therapy. At study conclusion, we will understand how to 1) effectively calculate heterogeneity in baseline mortality and poor outcome risk after moderate/severe TBI, 2) characterize how heterogeneity in PRO treatment moderates baseline risk and contributes to distinct, yet variable PRO response groups, 3) identify if/how post-randomization biomarkers are affected by PRO among treatment response groups 4) generate a parsimonious baseline risk calculator to test in other TBI populations in support of effective pre-randomization patient selection in future RCTs. Together this work incorporates baseline risk heterogeneity and HTE as key features in a precision medicine approach to informing PRO treatment response after TBI and for acute RCT TBI patient selection more generally.